The present disclosure relates generally to compositions and methods for targeting therapeutic agents. More particularly, the present disclosure relates to compositions and methods useful for targeting therapeutic agents to the neuromuscular junction using neuromuscular junction targeting peptides.
The neuromuscular junction is the point at which nerve signals the muscle to contract. More particularly, the neuromuscular junction is the synapse or junction of the axon terminal of a neuron with a muscle fiber plasma membrane.
Several diseases involve the neuromuscular junction as the primary site of injury. For example, myasthenia gravis is an autoimmune disorder that is caused by autoantibodies directed primarily toward the skeletal muscle acetylcholine receptor (AChR) at the neuromuscular junction. The antibodies bind to the post-synaptic surface of the neuromuscular junction and produce a reduction in AChR number and damage the muscle endplate, which leads to a failure of neuromuscular transmission that results in muscle weakness. Another category of gravis is caused by antibodies against muscle specific kinase (“MuSK”) at the neuromuscular junction. Lambert-Eaton syndrome is yet another disorder characterized by the attack of voltage-gated calcium channels at the neuromuscular junction by antibodies. Miller Fischer syndrome is another disorder involving the attack of nerve terminals by antibodies.
The complement system may underlie one effector mechanism for antibody-mediated immunity, which begins with antibody binding to a cell surface antigen and the formation of a membrane attack complex. The membrane attack complex is a multimeric protein complex that produces cell lysis and, in the case of myasthenia gravis, destruction of the neuromuscular junction. In antibody-initiated activation of the complement cascade, nascent C4b and C3b fragments condense with free hydroxyl and amino groups on biological membranes. Once bound, these fragments serve as sites for assembly of C4b2a and C3bBb, the central amplification enzymes of the cascade. Control of their activities to protect host tissues from autologous complement-mediated injury is through a system of cell-associated and serum regulatory proteins.
Complement inhibitors are a class of drugs that show promise for treating neuromuscular diseases. Complement inhibitors may stop the body's immune response system from attacking itself. Eculizumab, for example, is an anti-C5 antibody that is approved for use in paroxysmal nocturnal hemoglobinuria and in Phase 2 trials as a treatment for myasthenia gravis. Eculizumab functions by inhibiting complement. Because administration occurs by infusion, the agent may inhibit complement throughout the body.
Another complement inhibitor is rEV576 (OmCI or Conversin). rEV576 is an 18.5 kDa recombinantly produced protein derived from tick (Ornithodoros moubata) saliva that specifically inhibits C5 complement. rEV576 appears to directly bind C5 to prevent interaction with C5 convertase. Administration of rEV576 has been shown to reduce serum complement activity, diminish C9 deposition at the neuromuscular junction, and reduce cytotoxicity of serum from treated animals.
Therapies for myasthenia gravis generally focus on enhancing neuromuscular transmission by inhibition of cholinesterase using agents such as pyridostigmine. Other treatments such as corticosteroids, azathioprine, tacrolimus, and mycophenolate, are directed to suppressing or modulating the immune system. Acute exacerbations of weakness may be treated by plasmapheresis or intravenous immunoglobulins. While effective, these treatments can be expensive and may entail side affects that affect organ systems beyond the neuromuscular junction. These treatments may additionally result in systemic side effects because administration occurs throughout the body. The immunotherapies are not specifically focused on myasthenia gravis, but rather generally moderate immune response through reduction of autoantibody levels directly or indirectly through suppression of B and T cell activity.
Although treatments are available for conditions resulting from neuromuscular junction injury, there remains a concern over their efficacy, side-effects, and/or costs. Moreover, complement inhibitor strategies rely on systemic inhibition of complement. Accordingly, there exists a continued need to develop alternative treatments and methods for treating conditions resulting from neuromuscular junction injury.